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Pharmacotherapy of Pulmonary Hypertension pp 437–476Cite as

Anti-inflammatory and Immunosuppressive Agents in PAH

  • Chapter
  • First Online:

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 218))

Abstract

Pulmonary arterial hypertension (PAH) pathobiology involves a remodeling process in distal pulmonary arteries, as well as vasoconstriction and in situ thrombosis, leading to enhanced pulmonary vascular resistance and pressure, to right heart failure and death. The exact mechanisms accounting for PAH development remain unknown, but growing evidence demonstrate that inflammation plays a key role in triggering and maintaining pulmonary vascular remodeling. Not surprisingly, PAH is often associated with diverse inflammatory disorders. Furthermore, pathologic specimens from PAH patients reveal an accumulation of inflammatory cells in and around vascular lesions, including macrophages, T and B cells, dendritic cells, and mast cells. Circulating levels of autoantibodies, chemokines, and cytokines are also increased in PAH patients and some of these correlate with disease severity and patients’ outcome. Moreover, preclinical experiments demonstrated the key role of inflammation in PAH pathobiology. Immunosuppressive agents have also demonstrated beneficial effects in animal PAH models. In humans, observational studies suggested that immunosuppressive drugs may be effective in treating some PAH subtypes associated with marked inflammation. The present chapter reviews experimental and clinical evidence suggesting that inflammation is involved in the pathogenesis of PAH, as well the therapeutic potential of immunosuppressive agents in PAH.

Jolyane Meloche and Sébastien Renard have equally contributed to this work.

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Abbreviations

BMPRII:

Bone morphogenetic protein receptor 2

CCL:

C-C motif ligand

CsA:

Ciclosporin A

CTD:

Connective tissue disease

CYC:

Cyclophosphamide

DHEA:

Dehydroepiandrosterone

EC:

Endothelial cells

HAART:

Highly active antiretroviral therapy

HHV-8:

Human herpes virus 8

HIF-1α:

Hypoxia inducible factor 1 alpha

HIV:

Human immunodeficiency virus

IL:

Interleukin (i.e., IL-6, IL-2)

iPAH:

Idiopatic pulmonary arterial hypertension

MCP-1:

Monocyte chemotactic protein 1

MCT:

Monocrotaline (induced PAH)

MIP-1α:

Macrophage inflammatory protein 1 alpha

MMF:

Mycophenolate mofetil

MTX:

Methotrexate

NFAT:

Nuclear factor for activated T cells

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

PA:

Pulmonary artery

PAH:

Pulmonary arterial hypertension

PASMC:

Pulmonary artery smooth muscle cells

PDGF:

Platelet-derived growth factor

PH:

Pulmonary hypertension

RANTES:

Regulated upon activation normal T cell expressed and secreted

RV:

Right ventricle/ventricular

SLE:

Systemic lupus erythematosus

SSc:

Systemic scleroderma

Tc:

Cytotoxic T lymphocytes

Th:

Helper T lymphocytes

TNF-α:

Tumor necrosis factor alpha

Treg:

Regulatory T lymphocytes

VEGF:

Vascular endothelial growth factor

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Authors and Affiliations

  1. Department of Medicine, Laval University, Quebec City, QC, Canada

    Jolyane Meloche, Sébastien Renard, Steeve Provencher & Sébastien Bonnet

  2. Pulmonary Hypertension Research Group, Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, 2725 chemin Ste-Foy, Québec City, QC, Canada, G1V 4G5

    Jolyane Meloche, Sébastien Renard, Steeve Provencher & Sébastien Bonnet

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  1. Jolyane Meloche
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  4. Sébastien Bonnet
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  1. Faculte´ de Me´decine, Univ Paris-Sud, Le Kremlin Bicêtre, France

    Marc Humbert

  2. Dep of Anasthesia and Critical Care, Harvard Medical School Massachusetts General Hospital, Boston, Massachusetts, USA

    Oleg V. Evgenov

  3. Cardiovascular Research, Bayer Pharma AG, Wuppertal, Germany

    Johannes-Peter Stasch

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Meloche, J., Renard, S., Provencher, S., Bonnet, S. (2013). Anti-inflammatory and Immunosuppressive Agents in PAH. In: Humbert, M., Evgenov, O., Stasch, JP. (eds) Pharmacotherapy of Pulmonary Hypertension. Handbook of Experimental Pharmacology, vol 218. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38664-0_18

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